In 1995, the National Cancer Institute funded the Breast Cancer Family Registry (Breast CFR) established at six medical research institutions from the U.S., Canada, and Australia. The six sites, including the Northern California Family Registry for Breast Cancer (NC-FRBC), have developed an infrastructure and resources to facilitate and expedite a broad spectrum of multidisciplinary research, ranging from studies of the genetics and genetic epidemiology of breast cancer, including gene-gene and gene-environment interactions, to translational studies addressing clinical, behavioral, and preventive aspects of breast cancer. At the center of this infrastructure are data and biospecimens collected from over 13,000 breast and ovarian cancer families using standardized procedures and data collection instruments. Families across a broad spectrum of breast cancer risk have been recruited through population-based cancer registries (Northern California, Ontario (Canada), and Melbourne (Australia)) and through family cancer clinics and community outreach (New York City, Philadelphia, and Utah). The Colon Cancer Family Registry (C-CFR) is a multicenter infrastructure, initiated by NIH in 1997, with a goal of accelerating multidisciplinary discoveries on colorectal cancer causes, prevention, and outcomes. Registry data and biospecimens are accessible to qualified researchers around the world. The Registry, which is now reaching maturity, is successfully meeting its mandate, as 150 collaborative projects are already underway or completed and applications for use of the Registry are increasing rapidly. Within the last ten years, the six C-CFR centers have consented and enrolled over 11,000 mostly population-based families that span the continuum from average risk through very high risk. Families are enrolled using standardized protocols for collection of family history, epidemiologic risk factors, blood collection, tumor tissue collection, and baseline phenotyping of tumors for DMA mismatch repair proficiency. Data is transmitted to a central informatics center and data from completed research studies are also transmitted, so data on each family is increasingly annotated over time.